Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/19—Cytokines; Lymphokines; Interferons
  • A61K38/20—Interleukins [IL]
  • A61K38/2006—IL-1
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/16—Amides, e.g. hydroxamic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
  • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/65—Tetracyclines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/164—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
  • A61K38/1793—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents

Definitions

• the present invention relates to methods and compositions for preventing and/or treating pyelonephritis and/or urosepsis.
• Urinary tract infections are common and may be dangerous. The clinical presentation and severity varies depending on the site of infection and molecular basis of disease. In acute pyelonephritis (APN), bacteria ascend into the renal pelvis, where they cause an intense mucosal inflammatory response with progression into the renal parenchyma. Symptoms include high fever, malaise, loin pain as well as poor feeding and irritability in infants. APN can lead to urosepsis.
• APN acute pyelonephritis
• a pathogen-specific TLR4 response is activated by P fimbriated E. coli, through ceramide release and the successive phosphorylation of the TICAM-1 (TRIF) and TICAM-2 (TRAM) adaptors, CREB-1, c-FOS and c-JUN activates IRF- and API- dependent transcription. Additional involvement of MyD88, TIRAP and NF-kB depends on the virulence repertoire of the infecting strain. Genetic studies in the murine UTI model have identified IRF3-dependent gene expression and mCXCR2- dependent neutrophil activation as determinants of bacterial clearance and tissue homeostasis.
• Infected Irf3 v ⁇ or mCxcrl ⁇ mice develop severe APN and tissue damage after one week and relevance for human APN susceptibility has been demonstrated, through disease-associated IRF3 and CXCR1 polymorphisms in APN prone patients.
• agents that can be used to treat or prevent pyelonephritis, including APN, and as a result to prevent resulting urosepsis.
• Those agents include inhibitors of IL-1 receptors, particularly IL-ip, and NIpD proteins.
• MMP7 inhibitors and agents that moderate the expression of MMP7 may also be useful in the invention. It is particularly surprising that these agents, known for their anti-inflammatory activities can be used to treat infection.
• the present invention provides a method for preventing or treating pyelonephritis and I or urosepsis comprising administering to a patient in need thereof, an effective amount of an agent selected from the group consisting of IL-1 inhibitors, MMP inhibitors and NIpD proteins.
• the method or agent is for the treatment or prevention, preferably the treatment, of pyelonephritis.
• the pyelonephritis is acute pyelonephritis.
• the pyelonephritis is chronic or long-term.
• the method or agent is for the treatment or prevention, preferably the prevention, of urosepsis, particularly urosepsis caused by pyelonephritis.
• the agent may be provided in a pharmaceutical composition, comprising a pharmaceutically acceptable carrier.
• the agent is an IL-1 inhibitor.
• it is an IL-13 inhibitor.
• it is an IL-1 receptor antagonist inhibitor.
• Many IL-1 inhibitors are known in the art. These include, for example, small molecules such as anthraquinones, described for example in USP 4,244,968 including diacerein, as well as proteins and peptides such as an interleukin-1 receptor antagonist (IL-1 RA), for example anakinra and rilonacept, or pharmaceutically acceptable salts thereof, or prodrugs thereof, and combinations of these.
• the agent is an IL-ip receptor antagonist, such as anakinra (US Patent No 5,075,222).
• the agent is an MMP inhibitor, and in particular an MMP7 inhibitor.
• MMP inhibitors are known as described for example Durrant et al. Chem. Biol. Drug Des 20111; 78; 191-198, the content of which is incorporated herein by reference.
• batimastat particularly examples include batimastat, periostat (doxycycline hyclate), marimastat, or salts or prodrugs thereof, but in particular batimastat. It may also be an agent that reduces the expression of MMP, particularly MMP-7, such as a protein selected from ASC or NLRP-3, or an active fragment or variant thereof.
• the NIpD protein is a bacterial protein, preferably a commensal bacteria or asymptomatic carrier. In certain embodiments, this is a commensal bacteria or asymptomatic carrier with respect to a human host.
• the bacteria may be asymptomatic bacteriuria (ABU).
• the bacteria strain is an 5. coli strain, such as E. coli 83972.
• the NIpD protein may comprise or consist of SEQ ID NO: 1 or a variant or active fragment thereof.
• SEQ ID NO: 1 One particular fragment of SEQ ID NO: 1 is represented in bold (which is SEQ ID NO: 2).
• the NIpD protein, or variant or active fragment thereof is of low molecular weight, for instance less than 3kDa in molecular weight. In other embodiments, the proteins can be larger, for example about 40 kDa.
• fragment' refers to a peptide or protein which lacks one or more amino acids found in a full length protein but which still has the function of the full length protein.
• variant refers to proteins or polypeptides having a similar biological function but in which the amino acid sequence differs from the base sequence from which it is derived in that one or more amino acids within the sequence are substituted for other amino acids.
• Amino acid substitutions may be regarded as "conservative” where an amino acid is replaced with a different amino acid with broadly similar properties. Nonconservative substitutions are where amino acids are replaced with amino acids of a different type.
• Consative substitution means the substitution of an amino acid by another amino acid of the same class, in which the classes are defined as follows:
• Nonpolar A, V, L, I, P, M, F, W
• altering the primary structure of a polypeptide by a conservative substitution may not significantly alter the activity of that polypeptide because the side-chain of the amino acid which is inserted into the sequence may be able to form similar bonds and contacts as the side chain of the amino acid which has been substituted out. This is so even when the substitution is in a region which is critical in determining the peptide's conformation. Non-conservative substitutions are possible provided that these do not interrupt activity. Broadly speaking, fewer non-conservative substitutions will be possible without altering the biological activity of the polypeptides.
• Determination of the effect of any substitution is wholly within the routine capabilities of the skilled person, who can readily determine whether a variant polypeptide retains the fundamental properties and activity of the basic polypeptide. For example, when determining whether a variant of the polypeptide falls within the scope of the invention, the skilled person will determine whether the variant retains the biological activity of the native protein and whether the variant has at least 60%, preferably at least 70%, more preferably at least 80%, yet more preferably 90%, 95%, 96%, 97%, 98%, 99% or 100% activity of the native protein.
• Variants of the polypeptide may comprise or consist essentially of an amino acid sequence with at least 70% identity, for example at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 96%, 97%, 98% or 99% identity to a native polypeptide sequence.
• the level of sequence identity is suitably determined using the BLASTP computer program with the native polypeptide sequences as the base sequence. This means that native polypeptide sequences form the sequence against which the percentage identity is determined.
• the BLAST software is publicly available at http://blast.ncbi.nlm.nih.gov/Blast.cgi (accessible on 13 October 2016).
• the NIpD proteins may be isolated from bacteria. Where the NIpD protein is a variant or active fragment, it may be obtained by recombinant expression. Where the protein is obtained by recombinant expression, the protein sequence may comprise a sequence for use in purification, such as an N-terminal or C-terminal His tag. The use of purification tags is well-known in the art. In a preferred embodiment, the NIpD proteins, or variants or active fragments thereof, are synthetic. Typically, the NIpD protein, or variants or active fragments thereof, will be isolated or synthetic.
• the agent is suitably administered in the form of a pharmaceutical composition, which further comprise a pharmaceutically acceptable carrier.
• a pharmaceutical composition which further comprise a pharmaceutically acceptable carrier.
• Such compositions are known in the art.
• Suitable pharmaceutical compositions will be in either solid or liquid form. They may be adapted for administration by any convenient route, such as parenteral, oral or topical administration or for administration by inhalation or insufflation.
• the pharmaceutical acceptable carrier may include diluents or excipients which are physiologically tolerable and compatible with the active ingredient.
• compositions are prepared for injection, for example either subcutaneously or intravenously. They may be liquid solutions or suspensions, or they may be in the form of a solid that is suitable for solution in, or suspension in, liquid prior to injection. Suitable diluents and excipients are, for example, water, saline, dextrose, glycerol, or the like, and combinations thereof. In addition, if desired the compositions may contain minor amounts of auxiliary substances such as wetting or emulsifying agents, stabilizing or pH-buffering agents, and the like.
• Oral formulations will be in the form of solids or liquids, and may be solutions, syrups, suspensions, tablets, pills, capsules, sustained-release formulations, or powders.
• Oral formulations include such normally employed excipients as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like.
• Topical formulations will generally take the form of suppositories or intranasal aerosols.
• traditional binders and excipients may include, for example, polyalkylene glycols or triglycerides; such suppositories may be formed from mixtures containing the active ingredient.
• the amount of agent administered will vary depending upon factors such as the nature of the agent being used, the size and health of the patient, the nature of the condition being treated etc. in accordance with normal clinical practice. Typically, a dosage in the range of from g-50mg/Kg for instance from 2-20 mg/Kg, such as from 5- 15 mg/Kg would be expected to produce a suitable effect.
• Figure 1 shows the effect of NIpD and IL-IRA in infected mice, genetic model of acute pyelonephritis and urosepsis.
• Figure 1A shows the experimental protocol
• IB shows urine bacterial and neutrophil counts
• 1C shows kidney gross pathology at sacrifice day
• ID shows kidney bacterial numbers at sacrifice day.
• Irf3 ⁇ ⁇ mice were infected with E. coli CFT073 (50 pl of 2.10 9 cfu/ml) by intravesical instillation. Intraperitoneal treatment was administered daily, starting 6 hours after infection and for 7 days. Mice were treated with recombinant NIpD protein (105 pg in 100 pl) or IL- 1RA (Anakinra, 1 mg/kg, 100 pl). Control mice received PBS. Urine sampling for bacterial and neutrophil counts were done on day 1, 3, 5 and 7 in one group of animals (those sacrificed on day 7), and on day 1, 3, 5, 7, 21 and 42 in others.
• Urine bacterial and neutrophil counts Urine bacterial and neutrophil counts.
• Kidney bacterial numbers Kidney pathology in untreated mice was combined with high bacterial counts. Treated mice had very low or no kidney bacterial growth.

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• 2022
  • 2022-01-28 GB GBGB2201139.9A patent/GB202201139D0/en not_active Ceased
• 2023
  • 2023-01-27 CN CN202380030569.XA patent/CN119156222A/zh active Pending
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